Major Depressive Disorder (MDD) is one of the most disabling of all medical conditions worldwide with direct and indirect costs in the U.S. estimated to exceed $100 billion per year. The significance of this problem is reflected by the roughly 7 million depressed people that do not respond to classical anti-depressant treatment; termed treatment resistant depression (TRD) and suggests an alternative mechanism. Tumor Necrosis Factor (TNF) is reliably elevated in depressed patients and antagonism of TNF improves mood in patients with a variety of inflammatory diseases. A recent trial by our group demonstrated that a subset of TRD patients improved after treatment with the non-selective TNF antagonist infliximab. Moreover, plasma levels of the inflammatory C - reactive protein (CRP) >5mg/L predicted efficacy suggesting that CRP may be used as a biomarker. While these data are encouraging, use of infliximab and other commercially available non-selective TNF antagonists have significant liabilities; including an increased risk of immunosuppression and demyelinating neurologic disease. This occurs because these compounds inhibit both solTNF and transmembrane (tmTNF); solTNF drives chronic inflammatory disease while tmTNF facilitates host defense, synaptic plasticity, and myelination. XPro1595 is a novel, selective inhibitor of solTNF that readily crosses the BBB in therapeutic concentrations. Because XPro1595 does not interact with tmTNF it does not have the undesirable off-target effects associated with the currently available TNF inhibitors. XPro1595's ability to engage the target and superior safety profile make it an attractive candidate to treat TRD in patients with identifiable increased peripheral inflammation. Thus, this Phase I SBIR proposal seeks to establish preclinical proof-of-concept for the novel solTNF antagonist XPro1595 as therapy for patients with TRD and increased inflammation. The efficacy of XPro1595 will be examined and directly compared to the commercially available anti-TNF drug etanercept in terms of efficacy and target engagement in a rodent model of stress-induced depression with increased inflammation. As part of this application, we will also validate and expand upon the biomarker strategy. In addition to CRP, we will also examine plasma interleukin-6, and neutrophil gelatinase- associated lipocalin (NGAL), an inflammatory factor specific to solTNF that has been correlated with depression in elderly patients. Refinement of the biomarker strategy will increase the accuracy of identifying which TRD patients will have a therapeutic effect from anti-TNF therapy. This biomarker strategy is novel for psychiatry and represents an important step toward individualized medicine. Once complete, the results will provide justification to proceed to a Phase II proof-of-concept clinical trial in TRD patients with elevated peripheral blood biomarkers. In support of this, XPro1595 currently has an open FDA IND for RA that is directly transferable in support of potential clinical trials in depression.